Malignant hyperthermia

Harvey K Rosenbaum MD (Dr. Rosenbaum of the David Geffen School of Medicine at the University of California, Los Angeles has no relevant financial relationships to disclose.)
Dorothea Hall MD (Dr. Hall of the UCLA Department of Anesthesiology has no relevant financial relationships to disclose.)
Aravindhan Veerapandiyan MD, editor. (

Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.

Originally released September 6, 1993; last updated May 23, 2020; expires May 23, 2023

This article includes discussion of malignant hyperthermia, malignant hyperpyrexia, anesthetic-induced myopathy, masseter muscle rigidity (masseter spasm), as well as nonanesthetic rhabdomyolysis with or without hypermetabolism associated with mutations in RYR1 or CACNA1S. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Malignant hyperthermia is a pharmacogenetic disease that typically manifests during or immediately following general anesthesia. The authors discuss the disease and its diagnosis, including genetic testing. The primary mode of inheritance is autosomal dominant, although malignant hyperthermia does not always occur with each anesthetic exposure. Nonanesthesia related cases of severe rhabdomyolysis linked to hereditary neuromuscular disorders or RYR1 or CACNA1S mutations are reported in the literature with increasing frequency.

Without early identification and treatment, mortality is 70% or higher; thus, early diagnosis and treatment are lifesaving. However, early signs can be mistaken for inadequate anesthesia or for a febrile reaction of any cause. Thus, treatment must be started before the definitive diagnosis; in retrospect, many patients who are treated may not have malignant hyperthermia. Diagnosis of malignant hyperthermia for suspicious episodes may be excluded only by the caffeine halothane contracture test, which is performed at a limited number of centers in North America and requires fresh muscle tissue. Genetic testing is available at several designated centers. Despite ongoing advances, molecular genetic testing has limited sensitivity—it is used to confirm susceptibility to malignant hyperthermia rather than to clear patients of the diagnosis. Patients who are susceptible to malignant hyperthermia may receive general or regional anesthesia, but the anesthetic must be trigger-free, consisting of regional and local anesthetics or intravenous general anesthesia with or without nitrous oxide. The muscle relaxant succinylcholine and all potent inhalational agents carry a risk of triggering malignant hyperthermia in these patients. Reports of nonanesthetic-associated rhabdomyolysis, with or without hyperthermia, have been associated with malignant hyperthermia susceptible contracture tests or malignant hyperthermia-associated RYR1 mutations (Dlamini et al 2013; Molenaar et al 2014; Timmins et al 2015; Kraeva et al 2017; Zvaritch et al 2019). These patients represent a smaller subset of malignant hyperthermia susceptible individuals, given that most patients with anesthetic-induced malignant hyperthermia do not develop life-threatening hyperthermia or rhabdomyolysis with exercise or heat exposure.

Key points


• Malignant hyperthermia is a hypermetabolic response to potent inhalational agents and/or succinylcholine that can lead to death.


• Most patients have no signs or symptoms prior to a malignant hyperthermia crisis.


• Carriers may be at risk of nonanesthetic-related malignant hyperthermia or rhabdomyolysis triggered by heat, exertion, febrile illness, or a combination of these conditions.


• Dominant inheritance is mostly of RYR1 mutations.


RYR1 variants of unknown significance are not uncommon in an unselected population (ie, no history of malignant hyperthermia or myopathy).


• Early recognition, discontinuing triggers, treatment with dantrolene, and symptomatic therapy are critical.


• Adequate temperature monitoring has been associated with preventing death in analysis of malignant hyperthermia cases.


• For the known malignant hyperthermia-susceptible patient, general anesthesia is safe as long as known triggering agents are avoided.


• Family members must be identified to alert them about the potential risk.

Historical note and terminology

Malignant hyperthermia is a rare but potentially lethal complication of anesthesia. This syndrome was first identified in Australia in 1960. The proband had survived an anesthetic-induced syndrome characterized by hypotension, cyanosis, tachycardia, hyperthermia, and postoperative difficulty with movement. A family history of anesthesia-related deaths (10 of 24 relatives receiving anesthetics) suggested that this syndrome was an inherited disorder (Denborough et al 1962). An analogous syndrome occurs in various strains of pigs and is referred to as malignant hyperthermia, porcine stress syndrome, or pale, soft, exudative pork syndrome. Similar disorders have also been described in horses, dogs, and cats. Mice with knock-in of abnormal RyR1 have been produced and allow a better understanding of the syndrome (Yang 2006; Loy et al 2012; Eltit et al 2013). Malignant hyperthermia is associated with exposure to triggering agents—volatile anesthetics and/or succinylcholine, a depolarizing neuromuscular blocker—in otherwise normal patients (Rosenberg et al 2009; Zhou et al 2009). The observation that an in vitro contracture occurred in a muscle bundle in response to low doses of caffeine or halothane in individuals susceptible to malignant hyperthermia formed the basis for a diagnostic test and suggested that skeletal muscle was the target tissue. Genetic studies have demonstrated that malignant hyperthermia is a heterogeneous disorder (Robinson et al 2000).

Dantrolene was first synthesized in 1967 and accidentally found to have antispasmodic properties. Extensive work by Keith Ellis, a research scientist with a strong background in skeletal muscle physiology, confirmed that it caused dose-dependent muscle relaxation without significant side effects or cardiopulmonary depression. Ellis systematically narrowed down the site of action of dantrolene to involve intracellular calcium release. When he read about porcine stress syndrome and recognized that dantrolene was a potential treatment, he forwarded the drug to several researchers of malignant hyperthermia and, thus, pioneered its use as the life-saving treatment for malignant hyperthermia crises (Pollock et al 2017). Since then it has been established that dantrolene reduces calcium release or leak from RYR1-dependent intracellular stores; it also suppresses increased extracellular calcium entry and store overload-induced calcium release (Eltit et al 2013; Chen et al 2017).

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